David P. Kelsen

Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer.

BACKGROUND We performed a multi-institutional randomized trial comparing preoperative chemotherapy followed by surgery with surgery alone for patients with local and operable esophageal cancer. METHODS Preoperative chemotherapy for patients randomly assigned to the chemotherapy group included three cycles of cisplatin and fluorouracil. Surgery was performed two to four weeks after the completion of the third cycle; patients also received two additional cycles of chemotherapy after the operation. Patients randomly assigned to the immediate-surgery group underwent the same surgical procedure. The main end point was overall survival. RESULTS Of the 440 eligible patients with adequate data , 213 were assigned to receive preoperative chemotherapy and 227 to undergo immediate surgery. After a median possible study time of 55.4 months, there were no significant differences between the two groups in median survival: 14.9 months for the patients who received preoperative chemotherapy and 16.1 months for those who underwent immediate surgery (P=0.53). At one year, the survival rate was 59 percent for those who received chemotherapy and 60 percent for those who had surgery alone; at two years, survival was 35 percent and 37 percent, respectively. The toxic effects of chemotherapy were tolerable, and the addition of chemotherapy did not appear to increase the morbidity or mortality associated with surgery. There were no differences in survival between patients with squamous-cell carcinoma and those with adenocarcinoma. Weight loss was a significant predictor of poor outcome (P=0.03). With the addition of chemotherapy, there was no change in the rate of recurrence at locoregional or distant sites. CONCLUSIONS Preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with epidermoid cancer or adenocarcinoma of the esophagus.

Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry

PURPOSE To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). PATIENTS AND METHODS Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximabs commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria. RESULTS Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25%; 95% CI, 4% to 46%). CONCLUSION Colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not seem to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted.

Antiemetic Efficacy of High-Dose Metoclopramide: Randomized Trials with Placebo and Prochlorperazine in Patients with Chemotherapy-Induced Nausea and Vomiting

In a study of the effectiveness of high intravenous doses of metoclopramide as an antiemetic, 41 patients with advanced cancer who were being treated with cisplatin were entered into two double-blind trials. In the first trial patients were randomly assigned to receive either metoclopramide or placebo, and in the second trial they received either metoclopramide or prochlorperazine. Patients given metoclopramide had significantly fewer episodes of emesis than patients given placebo (medians, 1.0 vs. 10.5; P = 0.001) or prochlorperazine (medians, 1.5 vs. 12.0; P = 0.005). Metoclopramide was superior to placebo and to prochlorperazine in reducing the volume of emesis (P = 0.001 and P = 0.022, respectively) and was more effective than placebo in shortening the duration of nausea (P = 0.042) and vomiting (P = 0.028). Side effects from metoclopramide were minor, with mild sedation frequently observed; one patient had a brief extrapyramidal reaction. We conclude that metoclopramide in high intravenous doses has greater antiemetic activity than placebo or prochlorperazine in patients receiving cisplatin chemotherapy.

Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas.

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical acitivity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2–20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 × 103/μl (range 1.6–9.3) and the median absolute neutrophil (ANC) nadir was 2.0 × 103/μl (range 0.4–7.2). Thrombocytopenia - 100.0 × 103/μl was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0–245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemcitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.

Long-Term Results of RTOG Trial 8911 (USA Intergroup 113): A Random Assignment Trial Comparison of Chemotherapy Followed by Surgery Compared With Surgery Alone for Esophageal Cancer

PURPOSE We update Radiation Therapy Oncology Group trial 8911 (USA Intergroup 113), a comparison of chemotherapy plus surgery versus surgery alone for patients with localized esophageal cancer. The relationship between resection type and between tumor response and outcome were also analyzed. PATIENTS AND METHODS The chemotherapy group received preoperative cisplatin plus fluorouracil. Outcome based on the type of resection (R0, R1, R2, or no resection) was evaluated. The main end point was overall survival. Disease-free survival, relapse pattern, the influence of postoperative treatment, and the relationship between response to preoperative chemotherapy and outcome were also evaluated. RESULTS Two hundred sixteen patients received preoperative chemotherapy, 227 underwent immediate surgery. Fifty-nine percent of surgery only and 63% of chemotherapy plus surgery patients underwent R0 resections (P = .5137). Patients undergoing less than an R0 resection had an ominous prognosis; 32% of patients with R0 resections were alive and free of disease at 5 years, only 5% of patients undergoing an R1 resection survived for longer than 5 years. The median survival rates for patients with R1, R2, or no resections were not significantly different. While, as initially reported, there was no difference in overall survival for patients receiving perioperative chemotherapy compared with the surgery only group, patients with objective tumor regression after preoperative chemotherapy had improved survival. CONCLUSION For patients with localized esophageal cancer, whether or not preoperative chemotherapy is administered, only an R0 resection results in substantial long-term survival. Even microscopically positive margins are an ominous prognostic factor. After a R1 resection, postoperative chemoradiotherapy therapy offers the possibility of long-term disease-free survival to a small percentage of patients.

Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: A randomized trial investigating two dosage schedules

Eighty-five patients with advanced squamous carcinoma or adenocarcinoma of the lung were randomly assigned to receive vindesine with either high dose (120 mg/m2 of body surface area) or low dose (60 mg/m2) cisplatin. All patients had measurable disease and had not previously received chemotherapy. The response rate was similar with both treatments (43% complete and partial remission rate), but the high dose cisplatin regimen was superior to the low dose in median duration of response (12 versus 5.5 months; p = 0.05) and in median survival for responding patients (21.7 versus 10 months; p = 0.02). Myelosuppression was generally not a treatment problem; peripheral neuropathy and moderate azotemia were the major dose-limiting toxicities. With improved survival and response rates over those reported for conventional regimens, this combination of new agents supports the approach of new drug investigation in patients with lung cancer and the importance of the incorporation of active new agents into initial chemotherapy regimens.

Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin

Although many trials have evaluated the severity and treatment of nausea and vomiting immediately after cisplatin administration, no studies have focused on vomiting occurring more than 24 hours after chemotherapy--delayed emesis. Two consecutive trials were undertaken to evaluate the incidence, course (trial 1), and severity (trial 2) of delayed nausea and emesis and to develop methods to study these conditions. Eighty-six patients receiving cisplatin (120 mg/m2) for the first time were entered. On the day of cisplatin treatment, all received intravenous (IV) metoclopramide (3 mg/kg X 2 doses) plus dexamethasone (20 mg IV X 1 dose) with either diphenhydramine (50 mg IV) or lorazepam (1.0 to 1.5 mg/m2). Sixty-two percent of patients experienced no vomiting during the 24 hours immediately after administration of cisplatin. Overall, 93% of studied patients experienced some degree of delayed nausea or vomiting from 24 to 120 hours after cisplatin. In trial 1, the incidence of delayed vomiting ranged from 21% to 61% and delayed nausea from 24% to 78% in 58 patients. The highest incidence of both delayed nausea and emesis occurred during the period from 48 to 72 hours after administration of cisplatin. Patients who had no emesis during the initial 24 hours after cisplatin were less likely to experience delayed emesis. The severity of delayed nausea and vomiting was evaluated in 28 patients in trial 2. The amount of delayed nausea and vomiting was assessed daily by patients using a visual analogue scale and by an observer rating. The highest nausea and vomiting scores were seen during the period from 48 to 72 hours after administration of cisplatin, with acceptable correlation between patient scores and observer ratings. Although the nausea and vomiting occurring 24 or more hours after cisplatin administration is not as severe as that seen during the initial 24 hours after administration of cisplatin in patients not receiving antiemetics, it is a common condition that merits both further study and specific treatment.

FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer.

PURPOSE The chemotherapy regimens of high-dose methotrexate, high-dose fluorouracil (FU), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and leucovorin (FAMTX) and etoposide, Adriamycin, and cisplatin (EAP) have both been reported in nonrandom assignment trials to have high overall response rates and substantial complete response rates in patients with gastric cancer, as well as major toxicities of myelosuppression. Here we report a prospective, stratified, random-assignment comparison of the two combinations in previously untreated patients with advanced gastric cancer. PATIENTS AND METHODS Sixty patients were entered onto the trial, 30 receiving EAP and 30 FAMTX. All patients had measurable or assessable tumor masses. Patient entry was stopped at the point when significant toxicity differences were seen at interim analysis. RESULTS Response rates were similar between the two arms (FAMTX, 33% [95% confidence interval (CI), 16% to 50%]; EAP, 20% [95% Cl, 6% to 34%]). Three FAMTX and no EAP patients had complete remissions. The median survival for the two arms were similar (EAP, 6.1 months; FAMTX, 7.3 months). At 1 year, 7% of EAP and 17% of FAMTX patients were alive. EAP caused significantly more myelosuppression (leukopenia, P = .002; anemia, P = .03; thrombocytopenia, P = .0001) than did FAMTX. EAP also resulted in significantly longer hospitalizations per study month (8 v 5 days). Four EAP patients died of lethal toxicity, whereas no FAMTX patients died of treatment-related causes (P = .04). CONCLUSIONS FAMTX is at least as active as EAP and is significantly less toxic. Although both regimens remain investigational, the toxicities of FAMTX are more manageable. Further studies involving FAMTX in both the adjuvant and advanced disease setting are underway.

Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy.

PURPOSE To determine if fluorouracil (5-FU) plus high-dose leucovorin (LV) enhances local response in patients receiving preoperative radiation therapy (RT) for adenocarcinoma of the rectum, we compared the degree of downstaging in patients receiving preoperative RT with or without chemotherapy. PATIENTS AND METHODS For this comparison, three groups of patients who were treated with identical doses and techniques of preoperative pelvic RT (total dose of 5,040 cGy) were examined. Group 1 included 20 patients with unresectable disease who received combined RT and LV/5-FU. Group 2 included 11 patients with unresectable disease who received preoperative RT. Group 3 included 21 patients with invasive, resectable, primary disease who received preoperative RT. RESULTS Patients with unresectable disease who received LV/5-FU had a higher rate of pathologic complete response (20% v 0%) and a lower incidence of positive nodes (30% v 64%) compared with those who did not receive chemotherapy. Even when the most favorable group of patients was included (group 3), patients who received LV/5-FU still had a higher complete response rate (20% v 6%) and a lower incidence of positive nodes (30% v 53%) compared with those who received RT without LV/5-FU. Of those patients with initially unresectable disease, the resectability rate was higher in those who received LV/5-FU compared with those who did not receive LV/5-FU (90% v 64%). Patients who received LV/5-FU experienced slightly more grade 1 to 2 fatigue, stomatitis, nausea, and grade 3 diarrhea, tenesmus, and dysuria. CONCLUSIONS Despite the fact that patients who received chemotherapy (group 1) had more advanced disease compared with those with resectable disease (group 3), the addition of LV/5-FU increased the resectability and downstaging rates. The ultimate impact of a complete response as well as a decrease in the incidence of pelvic nodes on local control and survival remains to be determined. However, given the enhancement of down-staging in patients with unresectable rectal cancer, we are encouraged by the combined modality approach.

PRELIMINARY RESULTS OF PREOPERATIVE 5-FLUOROURACIL, LOW-DOSE LEUCOVORIN, AND CONCURRENT RADIATION THERAPY FOR CLINICALLY RESECTABLE T3 RECTAL CANCER

PURPOSE: We report the downstaging, sphincter preservation, acute toxicity, and preliminary local control and survival results of preoperative 5-fiuorouracil (5-FU), low-dose leucovorin (LV), and concurrent radiation therapy followed by postoperative LV/5-FU for treatment of patients with clinically resectable T3 rectal cancer. MATERIALS AND METHODS: A total of 32 patients received two monthly cycles of preoperative LV/5-FU (bolus daily×5). Radiation therapy (5,040 cGy) began concurrently on day 1. Postoperatively, patients received a median of two monthly cycles of LV/5-FU (range, 0–10). RESULTS: The complete response rate was 9 percent pathologic and 13 percent clinical, for a total of 22 percent. Total Grade 3+ acute toxicity during the preoperative combined modality segment was 25 percent (8/32). Of the 20 patients who were thought to initially require an abdominoperineal resection and for whom the intent of treatment was sphincter preservation, 17 (85 percent) were able to undergo sphincter-preserving surgery. With a median follow-up of 22 (3–59) months, none have developed local failure, and the three-year actuarial diseasefree survival rate was 60 percent. CONCLUSION: Our data reveal encouraging downstaging, sphincter preservation, and acute toxicity with this regimen. Additional follow-up is needed to assess the long-term local control and survival rates.